2, 3-imino-5alpha-androstan 17beta-ols and intermediates thereto



United States Patent 3,388,123 (OPTIONALLY 17-ALKYLATED) 2,3-IMINO-m-ANDROSTAN 17,6 0L5 AND INTERMEDI- ATES THERETO Paul D. Klimstra,Northbrook, IlL, assignor to G. D. Searle & Co., Chicago, 11]., acorporation of Delaware No Drawing. Filed Sept. 21, 1966, Set. No.580,888 Claims. (Cl. 260-2395) ABSTRACT OF THE DISCLOSURE (Optionally17-alkylated) 2,3-imino-5a-androstan-17,8- ols useful as pharmacologicalagents, in particular as androgenic and estrogeni inhibitory compounds.

The present invention is concerned with novel steroidal derivativescharacterized by a 2,3-irnino moiety and especially with (optionallyl7-alkylated) 2,3-imino-5a-androstan-l7t3-ols which are represented bythe following structural formula wherein R is symbolic of hydrogen or alower alkyl radical and Wavy lines indicate that the stere-ochemicalconfiguration of the imino group can be either 2a,3a or 2;3,3l3.

In the foregoing structural representation the lower alkyl radicalssymbolized by the R term are typified by methyl, ethyl, propyl, bu'tyl,pentyl, hexyl, heptyl and the branched-chain groups isomeric therewith.

The 2,3-imino compounds of this invention display valuablepharmacological properties. They are, for example, hormonal andanti-hormonal agents as is demonstrated by their androgenic andanti-estrogeni-c activity.

A method suitable for the manufacture of the novel compounds of thisinvention involves the use as starting materials of substancescharacterized by the following structural formula on, C

wherein W represents either a carbonyl or tit-(loweralkyl)-fi-hydroxymethylene group and the wavy lines, as hereinbefore,indicate the alternative :,30: or 2,8,35 stereochemical configuration.When the latter substances are contacted with a metallic azide in anaqueous medium containing a suitable inert water-miscible organicsolvent, cleavage of the epoxide ring occurs, thus resulting in thecorresponding 2,3-azido/hydroxy intermediates. That process isexemplified by the reaction of 2m,3a-ep0xy5aandrostan-l7-one or2;8,3;S-epoxy-17a-methyl-5m-androstan -l7,3-ol with sodium azide inaqueous dioxane to yield Zfl-azid0-3a-hydroxy Sa-androstan-17-one and3aazido-l7rx-methyl-5wandrOstane-ZB,17 9-diol, respectively.

The later 2,3-azido/hydroxy intermediates are then acyl- 3,388,123Patented June 11, 1968 atcd to form an ester whose oxygenated functionis readily removed. Sulfonyloxy and alkanoyloxy groups are especiallypref-erred. Those leaving" groups are exemplified by methanesulfonyloxy,ibenzenesulfonyloxy, p-toluenesulfonyloxy and acetoxy. A specificexample is the reaction of 2,8-azido-3m-hydroXy-Su-androStan-17-o11ewith methanesulfonyl chloride in pyridine, thus affording thecorresponding 3 methanesulfonate.

The foregoing 2,3-azido/acyloxy intermediates are converted to theinstant 2,3-imin-o compounds by reaction in a suitable reducing medium.Metallic hydride reducing agents such as lithium aluminum hydride,sodium borohydride and diisobutyl aluminum hydride are particularlyconvenient. 3o: azido-17a methyl-5wandrostane-Zfl,l7ddiolZ-methanesulfonate is thus converted to 2a,3u-imino-17ct-m6ti'lYi-50t-fll'ldl'OStal'l-17fl'01 by reaction with lithiumaluminum hydride in ether. That reduction can be accomplished also byuse of hydrazine in the presence of Raney nickel catalyst.Zfl-aZidO-Sa-andrOstane-Iia,l7fi-diol 3-methanesulfonate, for example,is heated with hydrazine hydrate in ethanol in the presence of Raneynickel catalyst to afford 219,3fl-iminodm-andr-ostan-l7fi-ol.

As indicated hereinbefore, the present invention en compasses also novelintermediates useful in the manufacture of the instant 2,3-iminocompounds. Those novel intermediates are represented by the followingstructural formula c H3 CH wherein R is as hereinbefore defined. Whenthose materials are allowed to react with silver cyanate and iodine, andthe intermediate 2p-isocyanato-3wiodo compounds are heated with a loweralkanol, the corresponding ZB-alkoxy-carbonylarnino-3wiodo substancesare produced. The latter substances are conveniently cyclized by heatingwith an alkaline reagent to produce the corresponding 2 33;3- irninocompound. Those processes are specifically illustrated by the reactionof l7a-methyl-5aandrost-2-en-17,6- 01 with silver cyanate and iodine,then with methanol to afford3a-iodo-Zfi-methoxycarbonylamino-17ot-methyl-5w androstan-l7B-ol andheating of the latter intermediate with potassium hydroxide in aqueousethanol, thus pro ducing 2,3,3,8imino-17a-methyl-5n-audrostan-l7fi-0l.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited eitherin spirit or in scope by the details contained therein as manymodifications both in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples, temperaturesare given in degrees centigrade C.). Quantities of materials areexpressed in parts by weight unless otherwise noted.

EXAMPLE 1 To a solution of 2 parts of 2oz,3a-epoxy-5a-undrostanli-one inparts of dioxane is added a solution of 0.7 part of sodium oxide in 3parts of water, and the rcsulting reaction mixture is heated at theretlux temperature for about 24 hours, then is poured into a mixture ofice and water. After stirring for about 30 minutes, the precipitatedsolid is collected by filtration, washed on the tilt-2r with Water anddried. Recrystallization from a mixture of hexane and acetone results inpure 2 fii-azido-3ahydroxy-5ot-androstan-l7-one, melting at about 164-l65.5. It is further characterized by an optical rotation of +l03 inchloroform.

To a solution of 5 parts of 2,8-t1ZidO-3a-hYdrOXY-5uandrostan-l'I-one inparts of pyridine, in a nitrogen atmosphere, is added, with cooling andstirring, 7.4 parts of methanesulfonyl chloride. The reaction mixture isstored at room temperature for about 16 hours, then is carefully pouredinto water. The precipitate which forms is collected by filtration andextracted into ether. The organic solution thus obtained is washedsuccessively with water, saturated aqueous ammonium chloride and water,then dried over anhydrous sodium sulfate containing dccolorizing carbonand stripped of solvent under reduced pressure. The resulting solidresidue is recrystallized from acetone-hexane to yield 23-azido-3a-hydroxy-5a-androstart-None 3-mcthanesulfonate, melting atabout 151- 153. This compound exhibits an optical rotation of +92.5 inchloroform and is further characterized by the following structuralformula Llli ll EXAMPLE 2 A solution of 1.5 parts ofIla-azido-3a-hydroxy-5ix-androstan-l7-one 3-mcthanesulfonate in 40.5parts of tetrahydrofuran is stirred and cooled at 0-5", and 3.5 parts oflithium tri-(tcrtiary-butoxy) aluminum hydride is added all at once. Theresulting reaction mixture is stirred for about 40 minutes, then ispoured into excess aqueous acetic acid. The resultin precipitated crudeproduct is collected on a filter, then is Washed with water and dried inair. Purification by recrystallization from aqueous acetone yields pureZp-aZidQ-Swandrostane-3a,17,8-diol 3- mcthancsulfonatc, melting at about104. This compound is furt er characterized by an optical rotation, inchloro- 4 form, of -i-45.5. It is represented by the followingstructural formula Clix t) H C ill I EXAMPLE 3 When an equivalentquantity of 25,3;3-epoxy-17amethyl-5a-androstan-17,6-0! is substitutedin the procedure of Example 1. there is produced3a-azido-l7a-methyl-5aandrostane-Zfi,l7 3-diol, melting at aboutl57l.58. This compound is represented by the following structuralformula I i --o1n EXAMPLE 4 To a solution of 8 parts of3a-azido-l7a-methyl-5aandrostane-Zti.l7li-diol in 40 parts of pyridine,in a nitrogen atmosphere, is added dropwise over a period of about 30minutes, with stirring and cooling, 3.55 parts of rnethanesulfonylchloride. Stirring is continued for about one hour longer, after whichtime the mixture is allowed to stand at room temperature for about 16hours. It is then carefully poured into a mixture of ice and water, andthe resulting aqueous mixture is extracted with ethyl acetate. Theorganic layer is separated, washed successively with water, dilutehydrochloric acid and dilute aqueous sodium bicarbonate, then dried overanhydrous sodium sulfate containing decolorizing carbon. The crudeproduct is obtained by distillation of the solvent under reducedpressure. The resulting solid residue is purified by recrystallizationfrom methanol to afford 3a-azidomethyl 5a androstane 23,1713 diolZ-methanesuli'onate, melting at about l94l96. This compound isrepresented by the following structural formula OH 7 H3 i ornsoio N4 1it EXAMPLE 5 A solution of 3 parts of2,8-azido-l7n-methyl-5a-androstane-3a,l7,8-diol in 15 parts of pyridineis stirred and cooled while 1.3 parts of methanesulfonyl chloride isadded. The reaction mixture is then stored at 0-5" for about 16 hours,after which time it is poured into a mixture of ice and water, then madeacidic by the addition of dilute hydrochloric acid. The gummy materialwhich forms is extracted into ether, and the ether solution isseparated, then washed successively with dilute hydro chloric acid anddilute sodium bicarbonate. Drying over anhydrous sodium sulfate followedby distillation of the solvent under reduced pressure affords aglass-like residue, which is purified by recrystallization from aqueousmethanol to yield pure ZB-azido-l7m-methyl-5a-androstane- 30:,l7fi-di0l3-methanesulfonate, melting at about 159- 161. This compound exhibits anoptical rotation of +29 in chloroform and is further characterized bythe following structural formula CILSO O EXAMPLE 6 EXAMPLE 7 Bysubstituting an equivalent quantity of 2 3,3,9-epoxy-17a-ethyl-5e-androstan-l7 3-01 and otherwise preceeding according to theprocess described in Example 1, there is produced 30: azido 17aethyI-Sa-andrOStane-Zfi,17/3- diol.

EXAMPLE 8 The substitution of an equivalent quantity of 3oc-3Zid0-l7a-ethyl-5ct-androstaneQfl,l7B-diol in the procedure described inExample 4 results in 3u-azido-17ot-ethy1-5aandr-ostane-2,6,17fi-diolZ-methanesulfonate.

EXAMPLE 9 Method A To a refluxing solution of 8 parts of2p-azido-5e-androstane-3e,17fi diol B-methanesulfonate in 240 parts ofethanol is added successively 41.2 parts of 100% hydrazine hydrate and0.5 part of Raney nickel. Refluxing of the resulting solution iscontinued for about 2 hours, after which time it is diluted with waterand cooled. Sodium chloride is added, and the aqueous mixture isextracted with ethyl acetate. The organic layer is separated, washedwith water, dried over anhydrous sodium sulfate and stripped of solventunder reduced pressure to afford an oil which solidifies upon standing.That crude material is dissolved in approximately 40 parts of isopropylalcohol, and the resulting solution is added to 24 parts of an isopropylalcohol solution containing 2 parts of maleic acid. Crystallization ofthe maleate salt is induced by cooling at 05 and dilution with ether.The crystals are collected by filtration, then dissolved in methanol,and a solution of 2 parts of potassium carbonate in 20 parts of water isadded. Dilution with water followed by cooling results in precipitationof the desired product, which is separated by filtration to afford25,313-imino- Sa-androstan-I'IB-oI, melting at about 98l02. Thiscompound is represented by the following structural formula 6 Method B Asolution of 3 parts of ZB-azidoh-hydroxy-Saandrostan-17-one3-methanesulfonate in 10 parts of dioxane, under nitrogen, is dilutedwith approximately parts of ether, and 4 parts of powdered lithiumaluminum hydride is added with stirring over a period of about 30minutes. The resulting reaction mixture is stirred at room temperaturefor about 5 hours, after which time wet ether and excess 30% aqueoussodium potassium tartrate are successively added. The ether layer isseparated by decantation, then is washed with water and dried overanhydrous sodium sulfate. Removal of the solvent by distillation underreduced pressure affords an oily residue which solidifies upon standing.Recrystallization of that c1ude solid from either ethyl acetate oraqueous methanol affords 25,36-imino-5a-androstan-1718-01, identicalwith the product of Method A.

EXAMPLE 10 To a solution of 3 parts of 17a-mcthyl-Sa-androst-Z- en-179-ol in 31.5 parts of tetrahydrofuran, under nitrogen, is added 4.4parts of silver cyanate (freshly prepared by the reaction of 25 parts ofsilver nitrate with 12.35 parts of potassium cyanate in 925 parts ofwater). The resulting slurry is cooled to approximately l5, then isstirred rapidly While 2.5 parts of iodine is added all at once. Thatreaction mixture is stirred for about 90 minutes at a temperature of 1Sto 10, then is stirred for about 16 hours at room temperature. Theprecipitated salts are removed by filtration through diatomaceous earthand are washed with 16 parts of methanol. The resulting filtrate isheated gently at the reflux temperature for about 4 hours, then isconcentrated to approximately one-fourth volume by distillation underreduced pressure. Dilution with cold water results in precipitation ofthe the product, which is collected by filtration, washed with water,then recrystallized from methanol to afford 3a iodo 17oz methyl 2,6methoxycarbonylaminodaandrostan-UB-ol, melting at about 168-175 withdecomposition.

A solution containing 4 parts of 3ot-iodo-17a-methyl-2fi-methoxycarbonylamino-5a-androstan-1 73-01, parts of ethanol, 20parts of water and 20 parts of potassium hydroxide is heated at thereflux temperature for about 2 hours, then is diluted with approximately650 parts of cold water. The precipitate which forms is collected byfiltration and extracted with a 1:1 mixture of isopropyl alcohol andether. To that ether solution is added 28 parts of an ethereal solutioncontaining one part of maleic acid. The precipitate which forms iscollected by filtration and dissolved in approximately 60 parts ofmethanol. To that organic solution is added a solution of 2 parts ofpotassium carbonate in 50 parts of water. Additional water is added inorder to precipitate the product, which is collected by filtration,washed on the filter with water and dried in air to yield2fi,3fi-imino-17a-methyl-5a-androstun-17501 methanolate. This compoundis represented by the following structural formula on cm l KL U EXAMPLE1 1 -ClItiOlI IIN:

EXAMPLE 12 When an equivalent quantity of2,6,3fl-epoxy-5a-androstand'F-one is substituted in the procedures ofExample 1, there are produced 3a-azido-2p-hydroxy-5aandrostand'fione and3u-azido-ZB-hydroxy-Se-androstanl7one Lmethanesulfonate.

The substitution of an equivalent quantity of Ila-azido-2p-hydroxy-5e-androstan-U-one Z-methanesulfonate in either of theprocedures of Example 9 results in 2a,3tximino-Se-androstan-17501.

EXAMPLE 13 When an equivalent quantity of 17u-ethyl-5ot-androst-Z-en-l'ifi-ol is substituted in the procedures of Example 10, there isproduced i7e-ethyl-25,3)8-imino-5a-androstan- 176-01.

EXAMPLE 14 wherein R is selected from the group consisting of hydrogenand a lower alkyl radical.

2. As in claim 1, a compound of the formula 0 it C H i tlower alkyl] KIN3. As in claim 1, the compound which is ZtLSfi-imino-17a-methyl-5a-androstan-17501.

4. As in claim 1, the compound which is 20:,3a-itt1i110- 17a-methyl-5a-androstan-17;?01.

5. A compound of the formula where X is selected from the group ofradicals consisting of azido, hydroxy and methanesulfonyloxy, Y isselected from the group of radicals consisting of azido andmethanesulfonyloxy with the provision that at least one but not both ofthe radicals represented by X and Y is, at the same time, azido and Z isselected from the group of radicals consisting of carbonyl,fl-hydroxymethylene and a-(lower alkyl)-,B-hydroxymethylene.

6. As in claim 5, a compound of the formula 0 H 0 lie, I

wherein X is selected from the group of radicals consisting of azido,hydroxy and methanesulfonyloxy and Y is selected from the group ofradicals consisting of azido and methanesulfonyloxy with the provisionthat at least one but not both of the radicals represented by X and Yis, at the same time azido.

7. As in claim 5, the compound which isZfl-azidodaandrostane-MJ'ifi-diol 3-methanesulfonate.

8. As in claim 5, the compound which is3a-azid0-17amethyl-SQc-andrOstane-ZB,lIB-diol.

9. As in claim 5, the compound which is3a-azido-l7amethyI-Sm-androstane-Zfi,17,8-diol Z-methanesulfonate.

10. As in claim 5, the compound which is2B-azid0-17amethyl-5ot-androstane-3a,I7 8-diol 3-metl1anesulfonate.

References Cited UNITED STATES PATENTS 3,238,194 3/1966 Klimstra et al260-2395 ELBERT L. ROBERTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,388,123 June 11, 1%3

Paul D. Klimstra It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected asshovm below: o1umn l line 14 "estrogeni inhibitory should read estrinhibigfiiry' lines 22 to 33 and column 7 lines 51 to 64 [he formulaseach occurrence should appear as shown below:

olumn l lines 49 to S8 the formula should appear as shown below:

olumn 2 lines 28 to 37 the formula should appear as shown below:

olumn 4 l ines 21 to 32 the formula should appear as shown below wlumn 8lines 2 to 12 the formula should' appear as shown dow:

51"? column 8 lines 17 to 26, the formula should appear as Shown below:

Signed and sealed this 3rd day of March 1970.

EAL] test:

EWARD M. FLETCHER JR. WILLIAM E. SCHUYLER, JR testing OfficerCommissioner of Patents

